Active ingredients, such as drugs or pharmaceuticals, may be prepared in a tablet form to allow for accurate and consistent dosing. However, this form of preparing and dispensing medications has many disadvantages including that a large proportion of adjuvants must be added to obtain a size able to be handled, that a larger medication form requires additional storage space, and that dispensing includes counting the tablets which has a tendency for inaccuracy. In addition, many persons, estimated to be as much as 28% of the population, have difficulty swallowing tablets. While tablets may be broken into smaller pieces or even crushed as a means of overcoming swallowing difficulties, this is not a suitable solution for many tablet or pill forms. For example, crushing or destroying the tablet or pill form to facilitate ingestion, alone or in admixture with food, may also destroy controlled release properties of the tablet or pill.
As an alternative to tablets and pills, films may be used to carry active ingredients such as drugs, pharmaceuticals, and the like. However, historically films and the process of making drug delivery systems therefrom have suffered from a number of unfavorable characteristics that have not allowed them to be used in practice. Further, films have limited space within which to include a sufficient dosage amount, given the high amount of polymer required to support the film. Films are additionally more difficult to keep stable, given that most of the product is exposed. Products such as tablets and pills are denser and may be coated, generally giving more stability. As such, films for many pharmaceuticals have generally been avoided.
Films that incorporate a pharmaceutically active ingredient are disclosed in expired U.S. Pat. No. 4,136,145 to Fuchs, et al. (“Fuchs”). These films may be formed into a sheet, dried and then cut into individual doses. The Fuchs disclosure alleges the fabrication of a uniform film, which includes the combination of water-soluble polymers, surfactants, flavors, sweeteners, plasticizers and drugs. These allegedly flexible films are disclosed as being useful for oral, topical or enteral use. Examples of specific uses disclosed by Fuchs include application of the films to mucosal membrane areas of the body, including the mouth, rectal, vaginal, nasal and ear areas.
The pharmaceutical compound tetrahydrolipstatin, also known as orlistat (trade name Xenical), (2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeranyloxy]-2-hexyl-3-hexadecanoic acid lactone, is indicated for treatment of obesity in humans. Tetrahydrolipstatin is a lipase inhibitor, blocking the absorption of approximately 30% of dietary fat. It is generally used for weight loss and weight management, and can also help prevent the onset of such diseases as type 2 diabetes, hypertension, and dyslipiemia.
Tetrahydrolipstatin is generally known in the art. For example, U.S. Pat. No. 4,598,089 teaches formation of the compound and its use as an effective obesity treatment pharmaceutical. U.S. Pat. No. 4,983,746 relates to a process for the artificial synthesis of orlistat which involves producing oxetanone derivatives; and esterification of the acid derivatives with an alcohol. Tetrahydrolipstatin is naturally stabilized in a crystalline structure.
Tetrahydrolipstatin is a very lipophilic compound, and is not readily dispersed into water. It is known to be very water-insoluble in its natural crystalline state. Its melting point is approximately 44-46° C. Those skilled in the art have attempted to develop new ways to manufacture tetrahydrolipstatin in its natural form. For example, U.S. Pat. No. 6,734,314 relates to a method of manufacturing tetrahydrolipstatin in a natural form.
Although small scale drug forms may have certain advantages, very few drugs are stable by nature in such a small scale form, such as in the form of nanoparticles or microparticles. Generally, when a drug has been formed in small-scale form, it is encapsulated within a softgel or hardgel capsule or tablet. However, the use of such drugs in the small-scale form has been generally limited to the use in a capsule-based or tablet-based system. For example, U.S. Pat. No. 6,004,996 discloses an attempt to stabilize tetrahydrolipstatin in a pellet. Until now, nanoparticles were made via processes such as milling or burning, which may drastically alter the chemical nature and effect of the active agent. Thus, stabilizing a drug in the small-scale form without disrupting the active effect of the agent is desired.
Therefore, there is a need for methods and compositions for preparing and stabilizing pharmaceutical compounds in a small-scale form without the need to encapsulate the compound in a tablet or capsule. Particularly, there is a need for methods and compositions for preparing and stabilizing pharmaceutical compounds in the form of nanoparticles or microparticles. There is further a need to prepare a drug dosage form which increases the apparent solubility of the drug. The stabilized, small-scale drugs can then be incorporated into other dosage forms, such as films. The present invention fulfills these and other needs, by preparing and stabilizing pharmaceutical compounds in the form of nanoparticles and/or microparticles.